Maternal Androgen-Related Conditions and Risk of ASD
Fetal exposure to elevated steroid sex hormone levels has been proposed to contribute to the development of ASD. While some support for this hypothesis comes from studies assessing in-utero androgen concentrations, measured levels may reflect androgens produced by the mother, placenta, or fetus. Thus, the possibility of reverse causation, i.e. that a fetus that will become a child with ASD produces more androgens than a typically developing fetus, rather than the high androgens causing the ASD, is difficult to rule-out. An association between high maternal androgen levels and ASD could more directly implicate androgen exposure as a causal factor. Previous publications reported associations between mothers with androgen-related conditions (namely polycystic ovary syndrome (PCOS) and hirsutism) and risk of ASD in progeny, but available data are limited and conflicting, and interpretation of the results is complicated by some evidence suggesting that direct transfer of maternal androgens to the fetus is restricted by the placental aromatase. This raises the possibility that any association between maternal hyperandrogenicity and ASD risk is mediated by other factors associated with maternal androgen excess, rather than being a direct result of the androgen hormones themselves.
To examine the association between PCOS, the primary cause of hyperandrogenicity in women of reproductive age, and risk of ASD in progeny, and to determine the extent to which this association is mediated by maternal androgen-related comorbidities such as metabolic and cardiovascular problems and use of infertility treatments. Additionally, to examine the association between risk of ASD and other maternal conditions that cause, or are caused by, excess androgens.
The study included 437,222 singleton births (4,022 with ASD) occurring between 1999 through 2013 in a large health fund in Israel. Data on ASD diagnoses, maternal androgen-related conditions and comorbidities, drug dispensing, and laboratory test results were obtained through 2016. Maternal conditions and ASD cases were identified through ICD-9 codes with further verification through review of medical records and laboratory results. Analyses of androgen-related conditions were performed using generalized estimating equation (GEE) models. Causal mediation analysis for multiple mediators using an imputation approach was performed to obtain natural direct and indirect effects of PCOS on ASD risk.
Children born to mothers diagnosed preconceptionally with PCOS (n= 17,922) had higher odds of ASD compared to children born to mothers without this condition (OR=1.28, 95%C.I:1.10-1.49). Elevated effects were also observed for other maternal conditions possibly caused by androgen excess, including acne, hirsutism, and infertility. Causal mediation analysis for PCOS indicated that mediation through any of the mediators considered accounted for approximately 1/5 of the total effect observed.
Results suggest a link between maternal PCOS as well as other androgen-related conditions and ASD risk in progeny, and additionally indicate that the observed effect is not entirely mediated by common comorbidities associated with excess androgens. Findings provide some support for a possible direct involvement of maternal hyperandrogenicity in ASD etiology. Alternatively, the observed effects could also be caused by other factors that affect maternal androgen homeostasis and fetal neurodevelopment though independent mechanisms.